Blood purifying apparatus

ABSTRACT

A blood purifying apparatus having excellent purification performance (elimination of low molecular proteins, etc.) and being contaminated with little endotoxins flowing from the dialyzate side is described. Attention was paid to the solute permeability coefficient α and water permeability performance Lp of blood purifying apparatus and the relation between α and Lp has been examined. As a result, a blood purifying apparatus having excellent purification performance and substantially being free from invasion of endotoxins was obtained by regulating the value α/Lp to 6×10 −7  or above, or regulating α within a range of 8×10 5  to 1.5×10 −3 , and the value α×Lp to 2.4×10 −2  or less. Also, a blood purifying apparatus having excellent purification performance and substantially being free from invasion of endotoxins was obtained by regulating the invasion ratio which is obtained by the polymer invasion test to 10% or less.

TECHNICAL FIELD

The present invention relates to a blood purifying apparatus with highblood treating capabilities such as elimination of low molecularproteins and the like, and, particularly, to a blood purifying apparatuswith reduced inflow of endotoxins from the dialyzate side.

BACKGROUND ART

Conventionally, a blood purifying apparatus used for hemodialysis,hemofiltration, and the like has an object of removing metabolicdecomposition products and toxic substances accumulated in the blood byapplying principle of diffusion or filtration. After development of adrum-type hemodialyzer by Kolff et al. in 1943, for example, membranetype dialyzers have been used for the therapy of patients who havepartially or completely lost kidney function.

Metabolic decomposition products and toxic substances are generallyeliminated through a membrane. Membranes made of regenerated celluloseor synthetic polymer such as polyethylene, polyacrylonitrile,polysulfone, or the like are known in the art. These materials arefabricated into membranes in the form of a sheet or hollow fiber. Thehollow fiber membranes have become more popular in recent years due tothe large blood contact area and high processing capacity.

If the membrane is in the form of a sheet, two or more sheets arelayered and-filled into a plastic container; if hollow fibers, severalhundred to several tens of thousands of pieces of fiber are bundled andfilled into a cylindrical plastic container to make semi manufacturedgoods, which is sterilized and used as blood purifying apparatus. Whenprocessing blood using a hollow fiber blood purifying apparatus, bloodis caused to flow inside hollow fibers and a dialyzate containing aninorganic electrolyte and the like is caused to flow outside the hollowfibers. Substances to be eliminated from blood are diffused or filteredthrough the hollow fiber membrane to the dialyzate side.

In the early stage, the materials to be eliminated by blood treatmentother than water retained in the body were low molecular weightinorganic substances such as urea nitrogen, creatinine, uric acid, andthe like. In 1965, Scribner proposed, in his middle molecularhypothesis, that it is necessary to eliminate substance having a certainlarge molecular weight for the maintenance of a normal state in patientswho have lost kidney function. In the later half of the 1980's, β2microglobulin (hereinafter referred to as β₂-Mg) which is a protein withan estimated molecular weight of 11,200 was found in the arthrogenousarea of a patient exhibiting dialysis amyloidosis which is a typicalsymptom of long-term dialysis patients. For these reasons, the recentmain stream is a high performance blood purifying apparatus which isdesigned to eliminate low molecular weight proteins having a molecularweight from about ten thousand to several tens of thousands.

The intended elimination of low molecular weight proteins such as β₂-Mgrequires expansion of membrane pore sizes to a certain degree. Excessivepore size expansion, however, accompanies problems such as escape ofalbumin (molecular weight: 66,000), which is a useful protein, andreverse filtration of dialyzate from the outside of the hollow fibers tothe inside where the blood flows. This may allow invasion of a verysmall amount of endotoxins contained in the dialyzate into the bloodside and may cause anaphylactogenic symptoms. Therefore, in manyclinical facilities an endotoxin adsorbent or an endotoxin eliminationfilter are provided immediately before the dialyzate side entrance ofthe dialyzer to control the dialyzate.

In dialyzers using an advanced high performance technology, however,these known technologies may encounter difficulties in sufficientlypreventing the effect of endotoxins when the endotoxin eliminationfilter and the like deteriorate or joints of dialyzate lines and thedialyzer are contaminated.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a blood purifyingapparatus having excellent blood-purification performance such aselimination performance of low molecular proteins and the like, andallowing only reduced inflow of endotoxins from the dialyzate side.

The inventors of the present invention have conducted extensive studieson the membrane structure and characteristics, and found that, even in ablood purifying apparatus with high elimination performance of lowmolecular weight proteins, it is possible to remarkably decreaseendotoxin inflow from the dialyzate side by adjusting the membranecharacteristics within certain specific values. This finding has led tothe completion of the invention.

Specifically, an object of the present invention is to provide a bloodpurifying apparatus in which (1) the value obtained by dividing thesolute permeability coefficient (α value) which is obtained by thepenetration test of a high weight moleculas substance, by the waterpermeability performance (Lp value) is 6×10⁻⁷ or more, (2) the solutepermeability coefficient (α value) is in the range of 8×10⁻⁵ to 1.5×10⁻³and the product of the solute permeability coefficient (α value) and thewater permeability performance (Lp value), which is obtained by thepolymer penetration test, is 2.4×10⁻² or less, or (3) the invasion ratioobtained by the invasion test of a high molecular weight substance is10% or less.

Another object of the present invention is to provide a blood purifyingapparatus satisfying two or more of the above three conditions at thesame time.

Still another object of the present invention is to provide a bloodpurifying apparatus satisfying any of the following conditions: the Lpvalue is in the range of 50 ml/Hr/mmHg/m² to 170 ml/Hr/mmHg/m²; an svalue obtained by the invasion test of a high molecular weight substanceis in the range of 1,000 to 5,000 and/or a p value obtained by theinvasion test of a high molecular weight substance is 6% or less; andthe blood purifying apparatus is made from an asymmetric hollow fibermembrane.

The blood purifying apparatus in the present invention is an artificialkidney which eliminates insoluble component in the blood by dialysisand/or filtration by causing the blood to contact with a dialyzate via amembrane such as a hemodialyzer, hemofilter, hemodialyis-filter, and thelike.

The penetration test of high-molecular substance in the presentinvention is a test comprising causing a solution of a water solublesubstance with a known high molecular weight to flow into the dialyzateside and detecting the amount of the dissolved substance permeating intothe blood side through the membrane. Polyvinylpyrrolidone (hereinafterreferred to as PVP) is used as the solute. PVP having a molecular weightdistribution in the range of several thousand to about 300,000 which ismade available by BASF under the trademark PVP(K-30) for example, issuitable for use in a test such as the present test in which the objectof evaluation is permeability of proteins with a molecular weight ofabout several tens of thousand or permeability of endotoxins with amolecular weight of about several hundred of thousands. In the presenttest, PVP having a weight average molecular weight of 35,000 is usedafter confirming the molecular weight distribution using HPLC. The PVPmay be from a single production lot or, if the molecular weightsignificantly differs from 35,000, two or more lots may be mixed toadjust the molecular weight distribution.

The method of conducting this test will now be described. A 20 ppm PVPsolution is prepared using PVP with a known molecular weight and is fedto a blood purifying apparatus after discharge of a washing liquid usedfor previous washing according to a normal washing procedure. The PVPsolution is caused to filtrate wholly from the dialyzate side to theblood side of the blood purifying apparatus at a rate of 100 ml/minute.The pressure difference between the dialyzate side and the blood sideafter five minutes from start of filtration is assumed to be ΔP (mmHg)The amount of the PVP solution obtained from the blood side for theduration of one minute after five minutes have elapsed from the start offiltration is measured, and the content of PVP in the solution isquantitatively determined by HPLC.

Permeability (%)=100×Blood side exit concentration÷Initial fluidconcentration  (1)

Lp in the present invention is the value defined by the followingformula (2). In the following formula (2), V (ml/min) is the amount ofPVP solution flowing out from the blood side exit during a period of oneminute after five minutes have elapsed from the start of filtration.

Lp (ml/Hr/mmHg/m²)=V×60÷ΔP÷Membrane area  (2)

The membrane area herein indicates the effective internal area (m²) ofthe blood purifying apparatus. αin the present invention indicates thevalue defined by the following formula (3).

α=Permeability÷Lp÷ΔP  (3)

The value α in this test is a parameter indicating the degree of easewith which the high molecular substances move from the dialyzate sideinto the blood side. In general, a larger value α is preferable forincreasing the efficiency of eliminating urinary poisonous substancesfrom the body because the capability of a membrane of eliminating asolute from the blood side to the dialyzate side has a positivecorrelation with the permeability of the solute from the dialyzate sideto the blood side. However, an excessively large value α accompanies anincrease in the amount of toxic substances such as endotoxins movinginto the blood side from the dialyzate side, which may induceanaphylactogenic symptoms.

Therefore, the inventors of the present invention have paid attention toboth the solute permeability coefficient α and the water permeabilityperformance Lp, and have conducted extensive studies on the relationshipbetween the values of α and Lp in the development of manufacturingconditions and structure of membrane. As a result, the inventors havefound that if the value (α/Lp) obtained by dividing a by Lp is 6×10⁻⁷ orgreater, a blood purifying apparatus (even if it is designed so as toeliminate unwanted substances with a relatively large molecular weightfrom the blood) allows only a very limited amount of endotoxins to movefrom the dialyzate side. The effect is remarkable when the value α/Lp is7.5×10⁻⁷ or greater, and particularly when 9×10⁻⁷ or greater. However,the value α/Lp should be less than 3×10⁻⁵ to achieve dialysis with asufficient water elimination capacity while causing albumin (molecularweight: 66,000), which is a useful substance in the blood, to permeatethrough the membrane in an amount as small as possible and minimizinginvasion of endotoxins.

Although the reason that the blood purifying apparatus satisfying theseconditions can achieve the object of the present invention is notnecessarily clear, it is assumed that delicate control of membranemanufacturing conditions ensures a certain balance between the solutepermeability and water permeability, resulting in the target membrane.

Blood purifying apparatus designed to exhibit a comparatively high waterpermeability are commonly used because of popular use of a UFRcontroller in the current dialysis treatment. In the blood purifyingapparatus of the present invention, two contradictory problems, one,improvement in the capability for eliminating unnecessary substances,and the other, inhibition of endotoxin invasion, can be solved at thesame time by setting the Lp value in the range of 50 ml/Hr/mmHg/m² to170 ml/Hr/mmHg/m² and the α/Lp value above 6×10⁻⁷ The range of 70ml/Hr/mmHg/m² to 110 ml/Hr/mmHg/m² is more preferable for the value Lp.

In addition, if the α value, which is the permeability of a solute, isset at 8×10⁻⁵ or above, while the above conditions are satisfied, theblood purifying apparatus may exhibit a greater capability foreliminating low molecular proteins and decreased inflow of endotoxinsfrom the dialyzate side. A more preferable α value is 9×10⁻⁵ or above,and particularly 10×10⁻⁵ or above. The upper limit of the value α inpractical use is 1.5×10⁻³ from the viewpoint of the mechanical strengthof the membrane.

Detailed investigation has revealed that a membrane with an asymmetricstructure having dense layers in inner surfaces and having holesexpanding toward the external surface achieves a greater capability ofeliminating low molecular proteins than a uniform membrane in which theholes in both internal and external surfaces are uniform.

Moreover, a blood purifying apparatus with a value α greater than 8×10⁻⁵and the product of α and Lp (α·Lp) less than 2.4×10⁻² has been found tominimize endotoxin invasion, while achieving high performance ineliminating low molecular proteins. When the solute permeabilitycoefficient α is less than 8×10⁻⁵ also in this instance, the eliminationperformance of low molecular weight proteins, for example, β₂-Mg, isimpaired, resulting in poor performance. If the pore size through whichuremic substances permeate is expanded or the number of holes isincreased to increase the α value, the value Lp which representspermeability of water increases. If the product of Lp and α is greaterthan 2.4×10⁻², endotoxins in the dialyzate tends to invade. Therefore, apreferable value of α is 9×10⁻⁵ or above, and particularly 10×10⁻⁵ orabove. The upper limit of the value α should be 1.5×10⁻³ from theviewpoint of ensuring mechanical strength. The reason is considered tobe that too many holes in the membrane may impair the strength.

A more preferable blood purifying apparatus will be achieved if thevalue Lp is in the range of 50 to 170 ml/Hr/mmHg/m², the value α isabove 8×10⁻⁵, and the product of Lp and α is 2.4×10⁻² or less. Moreover,a blood purifying apparatus with even better performance is expected ifthe value Lp is in the range of 70 to 110 ml/Hr/mmHg/m². If Lp is lessthan 50 ml/Hr/mmHg/m², water elimination performance may beinsufficient, resulting in impaired elimination of low molecularproteins of which the major part should be eliminated by filtration. Onthe other hand, if Lp is greater than 170 ml/Hr/mmHg/m², back-filtrationof water increases and the blood purifying apparatus tends to allowendotoxins in the dialyzate to invade the blood.

As a result of further investigation, the inventors have found that ablood purifying apparatus satisfying the ratio α/Lp in the range of8×10⁷ to 3×10⁵ in addition to the above conditions exhibits morepreferable performance. Specifically, it was discovered that the bloodpurifying apparatus not only exhibits performance excellent but alsoless invasion of endotoxins from the dialyzate side if the ratio α/Lp isgreater than 8×10⁻⁷. A more preferable value of the ratio α/Lp is from10×10⁻⁷ to 10×10⁻⁵, with an optimum range being from 11×10⁻⁷ to 3×10⁻⁶.If the ratio α/Lp is less than 8×10⁻⁷ or greater than 3×10⁻⁵, it appearsto be difficult to perform well-balanced dialysis in which the bloodpurifying apparatus exhibits sufficient water elimination performancewhile allowing only a minimal amount of albumin (molecular weight:66,000), which is a useful substance in the blood, to pass through themembrane.

A invasion test of a high molecular substance in the present inventionis a test for detecting invasion of PVP, with a weight average molecularweight of 35,000 used in the penetration test of a high molecularsubstance, by flowing a solution of PVP, from the dialyzate side intothe blood side. The following procedure was adopted in the presentinvention to reflect a more practical dialysis treatment and evaluatethe conditions immediately after initiation of dialysis.

Specifically, after filling the blood side with pure water, the entranceand exit of the blood are closed with forceps and the PVP solution iscaused to flow through the dialyzate side at a rate of 500 ml/minute.Then, pure water is caused to flow through the blood side at a rate of100 ml/minute and, at the same time, the forceps at the entrance andexit of the blood are eliminated. The amount of the discharged solutionfrom the blood exit side is determined for one minute after pure wateris caused to flow through the blood side. The total solution on theblood exit side is collected to determine the following characteristicsof the blood purifying apparatus.

The invasion ratio in the present invention is obtained by a highmolecular weight substance invasion test using the blood purifyingapparatus and indicates the value calculated by the following formula(4).

Invasion rate (%)=100×(Qd×Cd)/(Qb×Cb)  (4)

wherein, Qd indicates the rate of inflow into the dialyzate side(ml/min), Qb indicates the rate of outflow from the blood side (ml/min),Cd indicates the concentration of liquid flowing into the dialyzate side(ppm), and Cb indicates the concentration of liquid flowing out from theblood side (ppm).

The invasion ratio here indicates a parameter indicating the ratio ofPVP, a high molecular substance, invading the blood side to the totalamount of PVP which is supplied to the dialyzate side.

Although a major proportion of PVP used in the present invention has amolecular weight of 35,000, the PVP molecular weight has a distributionranging from several thousand to about 300,000. Therefore, the value pof the following formula can be determined by studying the data obtainedfrom the invasion test of a high molecular weight substance in moredetail, analyzing the chromatogram obtained by HPLC, and calculating theinvasion ratio of PVP with different molecular weights.

To determine the value p of the present invention, the values defined bythe following formula (5) is first determined.

s=(k1+k2)×20000÷2  (5)

wherein k1 indicates the invasion rate of a solute having a molecularweight of 20,000 and k2 indicates the invasion rate of a solute having amolecular weight of 40,000.

Then, the value p of the present invention is determined according tothe following formula (6).

p=(k3+k4)×20000÷2÷s×100  (6)

wherein k3 indicates the invasion rate of a solute having a molecularweight of 50,000 and k4 indicates the invasion rate of a solute having amolecular weight of 70,000.

The value s in this test is a parameter indicating the degree of easewith which PVP with a molecular weight of 20,000 to 40,000 invades fromthe dialyzate side. On the other hand, the value p is a parameterindicating the ratio of the degree of ease with which PVP with amolecular weight of 50,000 to 70,000 invades from the dialyzate side tothe values, which is a parameter indicating the degree of ease withwhich PVP with a molecular weight of 20,000 to 40,000 invades from thedialyzate side.

The present inventors have conducted detailed studies of the membranemanufacturing conditions and membrane structure, as well as the relationamong the invasion ratio, s value, and p value. As a result, theinventors have found that if the invasion ratio is kept to 10% or less,the blood purifying apparatus permits only a limited amount ofendotoxins to invade, notwithstanding the high performance ofeliminating low molecular proteins. Because the invasion ratio cannot bea negative value, as is clear from the definition, the lower limit ofthe invasion ratio satisfying the subject problem is 0% or more.

The reason that the membrane satisfying these conditions can achieve theobject of the present invention is assumed to be the fact that delicatecontrol of the membrane manufacturing conditions ensures bringingpermeability of the solute into a suitable range, resulting in thetarget membrane. However, the reason why the invasion ratio can be aneffective parameter to endotoxin invasion is not necessarily clear.Endotoxin, which is a compound having a molecular weight of about 8,700as minimum unit, is thought to be present in association, with two ormore units and having a molecular weight of slightly less than 20,000 toseveral hundred of thousands. Therefore, if PVP with an averagemolecular weight of 50,000 is used and its invasion ratio is as much asseveral percent, a considerable amount of endotoxins is estimated toinvade from the dialyzate side. Surprisingly, however, if endotoxininvasion is suppressed by maintaining the invasion ratio at 10% or less,this results in a dialyzer exhibiting substantially no invasion. Apreferable range of the invasion ratio is 9% or less, with 8% or lessbeing more preferable.

Moreover, it was discovered that more preferable results can be obtainedif the value s, which is a parameter indicating the degree of ease withwhich PVP with a molecular weight of 20,000 to 40,000 invades from thedialyzate side, is maintained at 1,000 or more. Specifically, the solutepermeability from the dialyzate side to the blood side represented bythe value s was found to indicate the solute elimination characteristicsfrom the blood side, which is inherent performance required for adialyzer. As a consequence, the elimination performance of low molecularproteins from the blood is improved by maintaining the value sat 1,000or above, thereby providing a more preferable resolution to the subject.Here, the greater the value s, the better the results because the values also represents solute elimination characteristics from the blood.However, the maximum value of s should be 5,000 for the membrane toperform dialysis while minimizing the amount of permeating albumin whichis a useful substance in the blood.

The range of the value s in the present invention is preferably 1,025 ormore, and more preferably 1,050 or more.

In addition, more detailed analysis of the invasion ratio at a highmolecular weight range revealed that more preferable results areavailable if a balance of the solute permeability of the dialyzer thatis shown by the value p is within a certain range. Specifically, the lowmolecular protein elimination performance can be increased bymaintaining the value p at 6% or less, resulting in a dialyzer withreduced endotoxin invasion, which is a target of the present invention.In the same manner as in the invasion ratio, the value p cannot be anegative value, as is clear from the definition. Its lower limit istherefore 0% or more. The range of the value P in the present inventionis preferably 5.8% or less, and more preferably 5.5% or less.

The present inventors have conducted more detailed studies on therelationship among the values α, Lp, the invasion ratio, s, and p. As aresult, it was found that if the vale α is maintained in the range of8×10⁻⁷ to 3×10⁻⁵, the product of α and Lp is less than 2.4×10⁻² and theinvasion ratio is kept at 10% or less, the blood purifying apparatuspermits only a limited amount of endotoxins to invade, notwithstandingthe high performance in eliminating low molecular proteins. Here,because the invasion ratio cannot be a negative value, as is clear fromthe definition, the lower limit of the invasion ratio satisfying thesubject problem is 0% or more.

Furthermore, more detailed analysis of the invasion ratio at a highmolecular weight range in the blood purifying apparatus satisfying theabove characteristics has revealed that more preferable results areobtained if a balance of the solute permeability of the blood purifyingapparatus that is shown by the value p is within a certain range.Specifically, a value of p of 6% or less not only can improve the lowmolecular protein elimination performance of the blood purifyingapparatus, but also ensure treatment without loss of albumin, which is auseful substance for the body, while permitting only a small amount ofendotoxins to invade the blood side. Thus, an ideal blood purifyingapparatus conforming to the objective of the present invention can beprovided. In the same manner as in the invasion ratio, the value pcannot be a negative value, as is clear from the definition. Its lowerlimit is therefore 0% or more. The range of the value p in the presentinvention is preferably 5.8% or less, and more preferably 5.5% or less.

As a result of further detailed studies, a blood purifying apparatuswith improved performance of eliminating low molecular proteins has beensuccessfully achieved while permitting only a limited amount ofendotoxins to invade, by maintaining the ratio α/Lp, that is, the valueα which is a solute permeability coefficient obtained by the polymerpenetration test, divided by the value Lp (ml/Hr/mmHg/m²) which is thewater permeability performance, at 6×10⁻⁷ or above, and by maintainingthe invasion ratio at 10% or less; or by maintaining the ratio α/Lp at6×10⁻⁷ or above, the value α in the range of 8×10⁷ to 3×10⁻⁵, theproduct of α and Lp at 2.4×10⁻² or less, and the invasion ratio at 10%or less.

There are no specific limitations to the material for the membrane usedfor the blood purifying apparatus of the present invention, so long assuch a material is applicable to blood purification. Examples of such amaterial include regenerated cellulose membranes, polysulfone membranesin which a hydrophilic polymer, such as PVP, polyvinyl alcohol,polyethylene glycol, etc., is incorporated for providing hydrophilicproperties, cellulose triacetate membranes, polymethylmethacrylatemembranes, polyacrylonitrile membranes, ethylene vinyl alcoholmembranes, and the like. A particularly preferable example is a hollowfiber membrane made from polysulfone with PVP added thereto. Althoughthe membrane may be of any form such as hollow fibers, a flat membrane,etc., hollow fibers are more preferable in order to enlarge the surfacearea with which the blood comes into contact.

The hollow fiber membrane made from polysulfone with PVP added theretopreferably used for blood purification in the present invention can beprepared by the following method, for example.

A spinning solution for the preparation of the membrane comprises 10 to20 wt % of polysulfone, 2 to 12 wt % of PVP, and solvents for thesepolymers. Any solvent which can dissolve both polysulfone and PVP, suchas dimethylacetamide, dimethylsulfoxide, N,N-dimethylformamide,N-methyl-2-pyrrolidone, etc. can be used either individually or as amixture of two or more in any ratio. Water and the like may be added asa non-solvent of polysulfone to the extent the polymer does notprecipitate.

In the membrane manufacturing process, after formation of polysulfonenuclei due to dispersion of the solvent and immersion in the non-solventfrom the spinning solution, aggregate particles are produced with PVPbeing present on the surface. Hollow fiber membranes with a dense layerformed on the side that comes into contact with the blood and asupporting layer formed on the other side are thus produced. Themembrane used for the blood purifying apparatus of the present inventionpreferably has a comparatively small number of large pores in the denselayer. For this reason, the rate of formation of the polysulfoneaggregate particles should preferably be controlled in the process ofmembrane manufacturing.

The present inventors have found that a blood purifying apparatus bywhich the object of the present invention is achieved can be provided bymanufacturing a hollow fiber membrane under stringently controlledconditions.

Specifically, the hollow fiber membrane for the blood purifyingapparatus of the present invention which satisfies the requirement forthe ratio α/Lp of 6×10⁻⁷ or above can be obtained by controlling theviscosity of the spinning solution in the range of 1,200 to 3,500 mPa·s,the concentration of a hydrophobic component, for example,dimethylacetamide, at 30% or higher, and the drafting ratio in the rangeof 1.1 to 1.9 in a known method of manufacturing hollow fiber membranes.

The hollow fiber membrane for the blood purifying apparatus whichsatisfies the requirements of the value α in the range of 8×10⁻⁵ to1.5×10⁻³ and the ratio α/Lp of 2.4×10⁻² or less can be obtained bycontrolling the viscosity of the spinning solution in the range of 2,800to 3,100 mPa·s by using a large proportion of hydrophilic componentssuch as PVP and water to hydrophobic components, with the drafting ratioin the range of 1.4 to 1.6. In this instance, a favorable result isobtained if the ratio of polysulfone/PVP in raw membrane solution isless than 1.7.

The hollow fiber membrane for the blood purifying apparatus of thepresent invention satisfying the conditions for an invasion ratio ofless than 10% can be manufactured by applying the same conditions asabove with respect to the spinning solution, viscosity, and draftingratio. To achieve a more preferable invasion ratio, the water content inthe spinning solution should be reduced (to as low as 1%, for example)or the water content in the hollow space producing agent should bedecreased.

The resulting hollow fiber membranes which satisfy these specificvarious conditions are processed by a known method to obtain hollowfiber membrane bundles. Specifically, the hollow fiber membranes arewound around a reel, cut into a prescribed length, and washed with hotwater. Then, a holder for a pore dimension such as an aqueous solutionof glycerol is attached, followed by drying under vacuum.

The resulting hollow fiber membrane bundles are filled into acylindrical plastic container, both ends are secured by adhesion with apotting agent, both terminals are cut, and the container is capped,thereby providing a half-finished product. The blood purifying apparatusof the present invention is obtained by attaching a plug to thehalf-finished product, as required, and sterilizing the container. It ispossible to fill the half-finished product container with pure water ora solution of a water-soluble substance such as sodium pyrosulfite,acetone sodium bisulfite, etc., then plug and sterilize the container.Sterilization with ethylene oxide gas or high pressure steam,sterilization with radiation such as γ-ray, and the like can bearbitrarily used as the method of sterilization.

The blood purifying apparatus thus manufactured exhibits highperformance such as elimination of low molecular proteins and the like,while allowing substantially no endotoxins to invade from the dialyzateside.

Best Mode for Carrying out the Invention

The present invention will be described in more detail by examples andcomparative examples, which are not intended to be limiting of thepresent invention.

The penetration test and invasion test of a high molecular weightsubstance, plasma performance evaluation test, and endotoxin test (ETtest) in the examples and comparative examples were carried out asfollows. In all tests, a washing operation was carried out using thesame physiological saline solution and the like as used in the dialysis.After discharging the washing solution, the following procedure wasperformed.

PVP of which the weight average molecular weight was confirmed to be35,000 by the measurement of molecular weight distribution using HPLC(LC9A manufactured by Shimazu Corp., analysis column, GF-310HQmanufactured by Showa Denko K. K.) was used for the penetration test andthe invasion test of high molecular weight substance.

<Penetration Test of a High Molecular Weight Substance>

PVP (K-30 manufactured by BASF) was used as a solute component, and a 20ppm aqueous solution of PVP was prepared for the determination of α, Lp,and ΔP. The aqueous PVP solution was caused to filtrate wholly from thedialyzate side to the blood side at a flow rate of 100 ml/min. Thepressure difference ΔP (mmHg) between the dialyzate side and the bloodside five minutes after initiation of filtration was determined. Theamount of PVP solution obtained from the blood side during the period ofone minute after five minutes had elapsed from the start of filtrationwas measured, and the content of PVP in the solution was quantitativelydetermined by HPLC (LC9A manufactured by Shimazu Corp., analysis column,GF-310HQ manufactured by Showa Denko K. K.). Permeability ratio wascalculated by use of the above formula (1).

The value Lp (ml/Hr/mmHg/m²) was calculated by applying the flow rate V(ml/min) of the PVP solution flowing out from the blood side exit duringthe period of one minute after five minutes had elapsed from theinitiation of filtration, and the pressure difference AP before andafter the membrane to the above formula (2).

Furthermore, the value α was determined from the above formula (3).

<Invasion Test of High Molecular Weight Substance>

As a solute component, a 20 ppm aqueous solution of PVP (K-30manufactured by BASF) was prepared. Measurement of the invasion ratiowas carried out according to the following procedure. Specifically,after filling the blood side with pure water, the entrance and exit forthe blood were closed with forceps and the PVP solution was caused toflow through the dialyzate side at a rate of 500 ml/minute. After threeminutes, pure water was caused to flow through the blood side at a rateof 100 ml/min and, at the same time, the forceps closing the entranceand exit for the blood were removed. The flow rate on the blood exitside one minute after the pure water was caused to flow through theblood side was measured and the total solution on the blood exit sidewas collected. The concentration of PVP in the solution flowing from theblood side was determined by HPLC (LC9A manufactured by Shimazu Corp.,analysis column, GF-310HQ manufactured by Showa Denko K. K.), and theinvasion ratio was calculated by applying the PVP concentration on theblood side and the original PVP concentration (20 ppm) to the formula(4)

The invasion ratio by molecular weight was determined by calculating theraw solution concentration and the blood exit side concentration foreach molecular weight from the GPC column calibration curve, thencalculating the value s and the value p respectively from the aboveformulas (5) and (6).

<Plasma Performance Evaluation Test>

(β₂-Mg Clearance)

The performance evaluation was carried out in accordance with the methodof the Japanese Society for Dialysis Therapy by causing cattle plasma(37° C., total protein content: 6.5 g/dl) in which β₂-Mg had beendissolved at a concentration of 1 mg/L to flow through the blood side ata flow rate of 200 ml/min for 60 minutes, then causing the dialyzate toflow through the dialyzate side at a flow rate of 500 ml/min. The flowrate of the filtrate per unit membrane area was 10 ml/min. 5 ml ofplasma sample was collected from the plasma entrance side and exit sideseven minutes after the dialyzate began to flow. The concentration ofβ₂-Mg in plasma was determined using imzain β₂-Mg (manufactured by FujiRebio Inc.) and the clearance was calculated according to the followingformula (7).

Clearance (ml/min)=(Cbi−Cbo)÷Cbi×Qbi  (7)

wherein Cbi indicates the concentration of solute at the entrance on theblood side, Cbo indicates the concentration of solute at the exit on theblood side, and Qbi indicates the flow rate at the entrance on the bloodside (ml/min)

(Albumin sieving coefficient)

In accordance with the method of the Japanese Society for DialysisTherapy cattle plasma (37° C., total protein content: 6.5 g/dl) wascaused to flow through the blood side at a flow rate of 200 ml/min for60 minutes, then the flow rate of the filtrate per unit membrane areawas set at 10 ml/min, without causing the dialyzate to flow. Plasmasamples at the plasma entrance side and exit side, and a sample offiltrate, 5 ml each, were collected seven minutes after the flow rate ofthe filtrate was controlled. The albumin concentration in the sampleswas determined by the laser nephelometry method and the albumin sievingcoefficient was calculated according to the following formula (8).

 Sieving coefficient=2Cf−(Cbi+Cbo)  (8)

wherein Cf indicates the concentration of solute at the filtrate side,Cbi indicates the concentration of solute at the entrance on the bloodside, and Cbo indicates the concentration of solute at the exit on theblood side.

(ET test)

Cattle plasma (37° C., total protein content: 6.5 g/dl) was caused toflow through the blood side at a flow rate of 100 ml/min. Then, thecattle plasma flow was stopped, and the blood side entrance and exitwere closed by forceps. After causing a dialyzate (37° C.), withendotoxins having been added in advance, was caused to flow through thedialyzate side at a rate of 500 ml/min for five minutes, the forceps onthe blood side were removed and the cattle plasma was caused to flow ata flow rate of 100 ml/min. One minute after the cattle plasma was causedto flow, 5 ml of plasma discharged from the blood exit side wascollected. Although the endotoxin concentration in a dialyzate used forclinical purpose is usually kept at a low level, the dialyzate used forthe evaluation of the effect of the present invention was prepared bymixing a concentrated endotoxin solution which was prepared by leavingtap water at 37° C. for several days and a commercially availabledialyzate, and adjusting the concentration to 5000 EU/L using Endospacy(ES-50 manufactured by Seikagaku Corp.). Et test was carried out usingthe dialyzate. The plasma obtained was treated by the PCA process toeliminate proteins and the endotoxin concentration in the plasma wasdetermined using Endospacy (ES-50 manufactured by Seikagaku Corp.).

EXAMPLE 1

17 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 9 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 74 wt % ofdimethylacetamide, and the solution was stirred for 10 hours to obtain aspinning solution for the manufacture of a membrane. The viscosity ofthe spinning solution was 2400 mPa·s at 45° C. Using a 30% aqueoussolution of dimethylacetamide as a hollow space producing agent, thespinning solution was injected from annular nozzles with a slit width of59.5 μm and run through a 60 cm dry zone at a spinning rate of 50 m/min.Before being wound, the spun hollow fiber was passed through acoagulating bath that was placed below the spinning nozzle and filledwith water. Because the amount of spinning solution injected wascontrolled so that the dry thickness of the hollow fiber membrane was 45μm, the discharge linear velocity of the spinning solution was 45.5m/min and the drafting rate was 1.1. Hollow fiber bundles thus woundaround a reel were cut and washed with hot water at 80° C. for 2 hours.The fiber bundles was adhered with glycerol aqueous solution and thendried under vacuum.

10,000 pieces of the hollow fiber membrane thus obtained was bundled andinserted into a cylindrical plastic container. Both ends of the hollowfibers were secured to the container using a polyurethane resin adhesiveand the excess ends were cut off. A cap for introducing blood wasprovided, thereby providing a module with an effective length of 25 cm.γ-rays at a dose of 25 kGy were applied to obtain the blood purifyingapparatus (effective membrane area: 1.5 m²) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 2

17 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 10 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 73 wt % ofdimethylacetamide, and the solution was stirred for 10 hours to obtain aspinning solution for the manufacture of a membrane. The viscosity ofthe spinning solution was 2650 mPa·s at 45° C. Using a 35% aqueoussolution of dimethylacetamide as a hollow space producing agent, thespinning solution was injected from annular nozzles with a slit width of59.5 μm and to run through a 60 cm dry zone at a spinning rate of 50m/min. Before being wound, the spun hollow fiber was passed through acoagulating bath that was placed below the spinning nozzle and filledwith water. Because the amount of spinning solution injected wascontrolled so that the dry thickness of the hollow fiber membrane was 45μm, the discharge linear velocity of the spinning solution was 26.3m/min and the drafting rate was 1.9. Hollow fiber bundles thus woundaround a reel were processed in the same manner as in Example 1 toobtain the blood purifying apparatus (effective membrane area: 1.5 m²)of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 3

18 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 9 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 73 wt % ofdimethylacetamide, and the solution was stirred for 10 hours to obtain aspinning solution for the manufacture of a membrane. The viscosity ofthe spinning solution was 3320 mPa·s at 45° C. Using a 32% aqueoussolution of dimethylacetamide as a hollow space producing agent, thespinning solution was injected from annular nozzles with a slit width of59.5 μm and to run through a 60 cm dry zone at a spinning rate of 50m/min. Before being wound, the spun hollow fiber was passed through acoagulating bath that was placed below the spinning nozzle and filledwith water. Because the amount of spinning solution injected wascontrolled so that the dry thickness of the hollow fiber membrane was 45μm, the discharge linear velocity of the spinning solution was 38.5m/min and the drafting rate was 1.3. Hollow fiber bundles thus woundaround a reel were processed in the same manner as in Example 1 toobtain the blood purifying apparatus (effective membrane area: 1.5 m²)of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 4

18 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 9 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 73 wt % ofdimethylacetamide, and the solution was stirred for 10 hours to obtain aspinning solution for the manufacture of a membrane. The viscosity ofthe spinning solution was 3200 mPa·s at 45° C. Using a 35% aqueoussolution of dimethylacetamide as a hollow space producing agent, thespinning solution was injected from annular nozzles with a slit width of59.5 μm and to run through a 60 cm dry zone at a spinning rate of 50m/min. Before being wound, the spun hollow fiber was passed through acoagulating bath that was placed below the spinning nozzle and filledwith water. Because the amount of spinning solution injected wascontrolled so that the dry thickness of the hollow fiber membrane was 45μm, the discharge linear velocity of the spinning solution was 27.8m/min and the drafting rate was 1.8. Hollow fiber bundles thus woundaround a reel were processed in the same manner as in Example 1 toobtain the blood purifying apparatus (effective membrane area: 1.5 m²)of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 5

16 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 10 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 72 wt % ofdimethylacetamide and 2 wt % of water, and the solution was stirred for10 hours to obtain a spinning solution for the manufacture of amembrane. The viscosity of the spinning solution was 2800 mPa·s at 45°C. Using a 35% aqueous solution of dimethylacetamide as a hollow spaceproducing agent, the spinning solution was injected from annular nozzleswith a slit width of 59.5 μm and to run through a 60 cm dry zone at aspinning rate of 50 m/min. Before being wound, the spun hollow fiber waspassed through a coagulating bath that was placed below the spinningnozzle and filled with water. Because the amount of spinning solutioninjected was controlled so that the dry thickness of the hollow fibermembrane was 45 μm, the discharge linear velocity of the spinningsolution was 35.7 m/min and the drafting rate was 1.4. Hollow fiberbundles thus wound around a reel were processed in the same manner as inExample 1 to obtain the blood purifying apparatus (effective membranearea: 1.5m²) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 6

16 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 10 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 73 wt % ofdimethylacetamide and 1 wt % of water, and the solution was stirred for10 hours to obtain a spinning solution for the manufacture of amembrane. The viscosity of the spinning solution was 2700 mPa·s at 45°C. Using a 35% aqueous solution of dimethylacetamide as a hollow spaceproducing agent, the spinning solution was injected from annular nozzleswith a slit width of 59.5 μm and to run through a 60 cm dry zone at aspinning rate of 50 m/min. Before being wound, the spun hollow fiber waspassed through a coagulating bath that was placed below the spinningnozzle and filled with water. Because the amount of spinning solutioninjected was controlled so that the dry thickness of the hollow fibermembrane was 45 μm, the discharge linear velocity of the spinningsolution was 33.3 m/min and the drafting rate was 1.5. Hollow fiberbundles thus wound around a reel were processed in the same manner as inExample 1 to obtain the blood purifying apparatus (effective membranearea: 1.5 m²) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 7

15 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 11 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 72 wt % ofdimethylacetamide and 2 wt % of water, and the solution was stirred for10 hours to obtain a spinning solution for the manufacture of amembrane. The viscosity of the spinning solution was 3100 mPa·s at 45°C. Using a 35% aqueous solution of dimethylacetamide as a hollow spaceproducing agent, the spinning solution was injected from annular nozzleswith a slit width of 59.5 μm and to run through a 60 cm dry zone at aspinning rate of 50 m/min. Before being wound, the spun hollow fiber waspassed through a coagulating bath that was placed below the spinningnozzle and filled with water. Because the amount of spinning solutioninjected was controlled so that the dry thickness of the hollow fibermembrane was 45 μm, the discharge linear velocity of the spinningsolution was 31.3 m/min and the drafting rate was 1.6. Hollow fiberbundles thus wound around a reel were processed in the same manner as inExample 1 to obtain the blood purifying apparatus (effective membranearea: 1.5 m²) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 8

15 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 11 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 72 wt % ofdimethylacetamide and 2 wt % of water, and the solution was stirred for10 hours to obtain a spinning solution for the manufacture of amembrane. The viscosity of the spinning solution was 3100 mPa·s at 45°C. Using a 35% aqueous solution of dimethylacetamide as a hollow spaceproducing agent, the spinning solution was injected from annular nozzleswith a slit width of 59.5 μm and to run through a 60 cm dry zone at aspinning rate of 50 m/min. Before being wound, the spun hollow fiber waspassed through a coagulating bath that was placed below the spinningnozzle and filled with water. Because the amount of spinning solutioninjected was controlled so that the dry thickness of the hollow fibermembrane was 45 μm, the discharge linear velocity of the spinningsolution was 35.7 m/min and the drafting rate was 1.4. Hollow fiberbundles thus wound around a reel were processed in the same manner as inExample 1 to obtain the blood purifying apparatus (effective membranearea: 1.5 m²) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

EXAMPLE 9

17 wt % of polysulfone (“P-1700” manufactured by AMOCO) and 11 wt % ofPVP (“K-90” manufactured by ISP) were dissolved in 72 wt % ofdimethylacetamide, and the solution was stirred for 10 hours to obtain aspinning solution for the manufacture of a membrane. The viscosity ofthe spinning solution was 3600 mPa·s at 45° C. Using a 40% aqueoussolution of dimethylacetamide as a hollow space producing agent, thespinning solution was injected from annular nozzles with a slit width of59.5 μm and to run through a 50 cm dry zone at a spinning rate of 50m/min. Before being wound, the spun hollow fiber was passed through acoagulating bath that was placed below the spinning nozzle and filledwith water. Because the amount of spinning solution injected wascontrolled so that the dry thickness of the hollow fiber membrane was 45μm, the discharge linear velocity of the spinning solution was 26.3m/min and the drafting rate was 1.9. Hollow fiber bundles thus woundaround a reel were processed in the same manner as in Example 1 toobtain the blood purifying apparatus (effective membrane area: 1.5 m²)of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

COMPARATIVE EXAMPLE 1

Using a 35% aqueous solution of dimethylacetamide as a hollow spaceproducing agent, the same spinning solution as used in Example 9 wasinjected from annular nozzles with a slit width of 50 μm and to runthrough a 60 cm dry zone at a spinning rate of 50 m/min. Before beingwound, the spun hollow fiber was passed through a coagulating bath thatwas placed below the spinning nozzle and filled with water. Because theamount of spinning solution injected was controlled so that the drythickness of the hollow fiber membrane was 45μm, the discharge linearvelocity of the spinning solution was 50.1 m/min and the drafting ratewas 1.0. Hollow fiber bundles thus wound around a reel were processed inthe same manner as in Example 1 to obtain the blood purifying apparatus(effective membrane area: 1.5 m) of the present invention.

The penetration test and invasion test of a high molecular weightsubstance, ET test, and plasma performance evaluation test were carriedout using the obtained blood purifying apparatus. The results are shownin Table 1.

TABLE 1 Invasion β₂-Mg Albumin sieving ET α/Lp Lp α α × Lp rate s ρclearance coefficient concentration Example 1 6.49 × 10⁻⁷ 203.3 1.32 ×10⁻⁴ 2.68 × 10⁻² 11.6% 1940.8 15.6% 54.3 0.024 0.054 Example 2 8.10 ×10⁻⁷ 192.5 1.56 × 10⁻⁴ 3.54 × 10⁻² 12.4% 6111.7 17.2% 59.5 0.031 0.055Example 3 1.05 × 10⁻⁶ 167.9 1.77 × 10⁻⁴ 2.97 × 10⁻² 16.6% 5529.4 55.4%58.2 0.044 0.042 Example 4 9.01 × 10⁻⁷ 163.2 1.47 × 10⁻⁴ 2.40 × 10⁻²15.4% 3490.2 50.4% 57.2 0.030 0.051 Example 5 1.10 × 10⁻⁶ 110.4 1.21 ×10⁻⁴ 1.34 × 10⁻²  9.7% 5029.3  6.8% 56.9 0.026 0.028 Example 6 8.71 ×10⁻⁷ 108.1 9.42 × 10⁻⁵ 1.02 × 10⁻²  7.6% 1120.2  6.1% 51.5 0.011 0.018Example 7 1.51 × 10⁻⁶ 119.5 1.81 × 10⁻⁴ 2.16 × 10⁻²  9.1% 4942.1  8.9%62.8 0.020 0.024 Example 8 1.17 × 10⁻⁶ 88.9 1.04 × 10⁻⁴ 9.25 × 10⁻³ 5.8% 1074.0  5.3% 62.6 0.001 0.011 Example 9 7.22 × 10⁻⁶ 108.1 7.81 ×10⁻⁵ 8.44 × 10⁻³  5.4% 669.4  0.6% 49.8 0.012 0.009 Comparative 5.60 ×10⁻⁷ 221.4 1.24 × 10⁻⁴ 2.75 × 10⁻² 19.4% 5681.3 28.9% 56.2 0.048 0.551Example 1 Unit: Lp value ml/Hr/mmHg/m² Invasion rate % ρ value % β₂-Mgclearance ml/min ET concentration EU/ml

What is claimed is:
 1. A blood purifying apparatus wherein a ratio α/Lpis in a range of 6×10⁻⁷ to 3×10⁻⁵, said value obtained by a solutepermeability coefficient α(Hr·m²/ml), which is obtained by a penetrationtest of a high molecular weight substance, being divided by waterpermeability performance Lp (ml/Hr/mmHg/m²) which is in a range of 50 to170.
 2. The blood purifying apparatus according to claim 1, wherein thesolute permeability coefficient α is 8×10⁻⁵ or more.
 3. The bloodpurifying apparatus according to claim 1, wherein the solutepermeability coefficient α, which is obtained by a penetration test of ahigh molecular weight substance, is in a range of 8×10⁻⁵ to 1.5×10⁻³,and the product of the solute transmission coefficient α and the waterpermeability performance Lp, which is obtained by the same test, is2.4×10⁻² or less.
 4. A blood purifying apparatus wherein a solutepermeability coefficient o(Hr·m²/ml), which is obtained by a penetrationtest of a high molecular weight substance, is in a range of 8×10⁻⁵ to1.5×10⁻³, and the product of the solute permeability coefficient α andthe water permeability performance Lp (ml/Hr/mmHg/m²), which is obtainedby said test, is in the range of more than 0 to 2.4×10⁻².
 5. The bloodpurifying apparatus according to claim 4, wherein the water permeabilityperformance Lp (ml/Hr/mmHg/m²) is in a range of 50 to
 170. 6. A bloodpurifying apparatus in which an invasion ratio is obtained by aninvasion test of a high molecular weight substance in a range of 0% to10%.
 7. The blood purifying apparatus according to claim 6, wherein thes value obtained by the invasion test is in a range of 1,000 to 5,000.8. The blood purifying apparatus according to claim 6, wherein the pvalue obtained by an invasion test is in a range of 0% to 6%.
 9. Theblood purifying apparatus according to claim 6, wherein the solutepermeability coefficient α(Hr·m²/ml) which is obtained by thepenetration test of a high molecular weight substance, is in the rangeof 8×10⁻⁵ to 1.5×10⁻³, and the product of the solute permeabilitycoefficient α and the water permeability performance Lp (ml/Hr/mmHg/m²),which is obtained by the same test, is 2.4×10⁻² or less.
 10. The bloodpurifying apparatus according to claim 6, wherein the ratio α/Lp is inthe range of 6×10⁻⁷ to 3×10⁻⁵ and the water permeability performance Lp(ml/Hr/mmHg/m²) is in a range of 50 to
 170. 11. The blood purifyingapparatus according to claim 1, comprising a hollow fiber membranehaving an asymmetric structure.
 12. The blood purifying apparatusaccording to claim 9, wherein the ratio α/Lp, a solute permeabilitycoefficient α(Hr·m²/ml) which is obtained by the penetration test of ahigh molecular weight substance, being divided by water permeabilityperformance Lp (ml/Hr/mmHg/m²), is 6×10⁻⁷ or more.